PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurodegenerative condition for which accurate and timely diagnosis is key for optimal intervention and for guiding treatment when disease-modifying therapies become available. Olfactory dysfunction is a core preclinical sign of AD that predicts conversion from mild cognitive impairment (MCI) to AD with high sensitivity and specificity. The olfactory system is among the earliest brain regions to demonstrate AD pathology and is the only sensory system that provides direct access to the entorhinal cortex (ERC) and hippocampus, medial temporal lobe (MTL) structures critically important for cognitive and memory decline in AD and MCI. Despite the relevance of olfactory dysfunction to the pathophysiology of AD, the neurobiological underpinnings of olfactory impairment remain poorly understood. To date, clinical evaluation of olfaction has been limited to psychophysical assessment, which is subjective and uninformative regarding underlying physiological abnormalities of the olfactory system. We have developed advanced 7T MRI methods to examine olfactory dysfunction and will use these methods to investigate microvascular and metabolic changes of the olfactory system in prodromal Alzheimer's disease patients and controls. In Aims 1 and 2, we will examine abnormalities in microvascular and metabolic parameters at rest and during olfactory stimulation. Importantly, we will quantify each individual microvascular and metabolic parameter for different blood vessel types (arterioles in particular) separately. These indices will be more biologically meaningful than the relatively global, nonspecific indicators of compromised olfactory function obtained from the behavioral tests. In Aim 3, we will assess the relationship between neurovascular abnormalities of the olfactory system and: olfactory behavioral measures; structural changes measured by MRI; and established CSF biomarkers of AD, including beta amyloid, tau and phosphorylated tau. A longitudinal follow-up of the cognitive measures will be collected after 2 years for all the participants, which will be used to evaluate whether the MRI measures at the initial visit are predictive for cognitive decline in these subjects. This work will significantly advance our understanding of the microvascular and metabolic changes associated with olfactory impairment in MCI. The MRI measures used here are noninvasive, repeatable for longitudinal investigations, and can be performed with high spatial resolution in humans. Results from the proposed studies can facilitate the development of biomarkers for early identification and prediction of AD and also has the potential to inform treatment studies for early intervention in AD.